JPS5821624B2 - 3 Candiphenylamine - Yudou Taino Seihou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a 3-ring diphthalate compound of the general formula I: [wherein R1 represents a straight-chain or branched alkyl group optionally substituted with a carboxyl group or an alkoxycarbonyl group] Regarding the production method of nylamine derivatives and their pharmaceutically acceptable salts, the general formula (
It is also within the scope of the invention to use the compounds of I) for preparing pharmaceutical preparations.

The alkyl group R1 is preferably branched and can have 1 to 8 carbon atoms, preferably 3 to 5 carbon atoms, and the alkyl group in the alkoxycarbonyl group has 1 to 6 carbon atoms. , advantageously 1 to 3.

It has been found that this new compound blocks the activity of β-receptors of the sympathetic nervous system and is therefore suitable for the treatment or prevention of coronary artery disease.

Particularly effective are the aforementioned compounds I in which R1 is a branched alkyl group optionally substituted by a carboxyl group and an alkoxycarbonyl group.

The method for producing the compound of the general formula (III) according to the present invention is carried out by a method known per se. , the other is a reactive group and R2 represents a hydrogen atom, the unveiling Y and R2 may together represent an atomic marker (, R3 represents the same as R1 or represents hydrogen, X or (b) a 3-ring diphynylamine derivative of the formula ■: is reacted with a compound of the formula ■: [wherein Y, R2 and R3 are as defined above], and then If the group R1 is optionally introduced later by alkylation, and R1 is substituted by a carboxy group or an alkoxycarbonyl group, it is converted in any manner by saponification, esterification or ester substitution, optionally thus It is characterized by converting the obtained compound of general formula (1) into its pharmaceutically acceptable salt.

The reactive groups Y and Z in the compounds of formulas 1 and 2 are in particular acid groups, for example of hydrohalic acid and sulfonic acid.

The reaction of a compound of formula (1) with a compound of formula (1) according to process (a) and a compound of formula (1) and a compound of formula (1) according to process (b) is preferably carried out in a polar solvent, such as methanol, ethanol or dioxane. It will be held in

The reaction can also be brought about by mixing molar amounts of the reactants and standing at room temperature; the reaction can optionally be accelerated by brief heating in a pressure vessel.

The reaction of a compound of formula (1) with a substance of formula (2) according to process (b) is preferably carried out in the presence of an acid acceptor.

However, it is also possible to use alkali salts of hydroxy compounds of formula (1).

to be optionally carried out to give a compound of formula I,
Subsequent N-alkylation (if R3 represents hydrogen in the substances of formulas 1 and 2 used as starting compounds)
can be carried out in conventional manner, advantageously using reactive alkyl compounds, such as alkyl halides or dialkyl sulfates.

Advantageously, the reaction components are heated in an organic solvent, such as ethanol, in the presence of a base, such as sodium carbonate or potassium carbonate.

To prepare compounds of the formula I according to the invention in which R1 represents a branched alkyl group, the alkylation of the amine group is preferably carried out by reaction with a suitable ketone under reducing conditions.

In this case, preference is given to using catalytic hydrogenation using Raney nickel or platinum metal catalysts.

The hydrogenation is carried out in an inert solvent or in an excess of ketone.

Alkylation can also be carried out with an excess of carbonyl compound in the presence of an alkali borohydride.

It is advantageous to operate at room temperature or at moderately elevated temperatures.

The saponification of compounds I in which R1 represents an alkoxycarbonylalkyl group is carried out using hydrous acids or bases in a manner known per se.

Esterification of compounds in which R1 represents a carboxyalkyl group can be carried out using an excess of the alcohol in question, such as methanol, ethanol, glopanol, inpropyl alcohol, nibutyl alcohol, under dehydrating conditions.

Dehydration of the reaction mixture was carried out using an entrainer (5chlepp
This can be achieved by azeotropic distillation using solvents (eg methylene chloride, penzol) serving as er ) or by addition of dehydrating agents (eg concentrated sulfuric acid, boron trifluoride etherate).

In principle, it is also possible to alkylate carboxyl groups with diazoalkanes.

The transesterification of compound (2) in which R1 represents an alkoxycarbonylalkyl group can be carried out by reaction with an excess of the appropriate alcohol.

In order to convert a compound of general formula I into its pharmaceutically acceptable salt, the compound is preferably dissolved in an organic solvent, in an equivalent amount of an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, phosphoric acid. , sulfuric acid, acetic acid, salicylic acid, citric acid, benzoic acid, naphthoic acid, 0-acetoxybenzoic acid, adipic acid or maleic acid, or in the case of carboxy derivatives, e.g. alkali and alkaline earth bases. , neutralize with ammonia or organic amine.

The novel substances (1) and their salts according to the invention can be applied orally or parenterally in liquid or solid form.

Advantageously, as an injection medium, a stabilizer. Water is used containing additives commonly used in injection solutions such as solubility aids or buffers.

Such additives include, for example, tartrate and citrate buffers, ethanol, complexing agents (e.g. ethylenediaminetetraacetic acid and its non-toxic salts), high molecular weight polymers for viscosity control (e.g. liquid polyoxyethylene ).

Solid excipients include, for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acid, polymeric fatty acids (eg stearic acid), gelatin, agar, calcium phosphate,
Magnesium stearate, animal and vegetable fats and solid polymers (e.g. polyethylene glycol)
and preparations suitable for oral application may contain flavoring and sweetening agents, if desired.

Next, the method for producing the novel substance according to the present invention will be explained in detail with reference to Examples.

Example 1 2-(3-Isopropylamino-2-hydroxy-propoxy)-carbazoleTo a solution of 147 2-(2,3-epoxy-propoxy)-carbazole in 125 ml dioxane was added 60 ml isopropylamine and refluxed for 7 hours. Heat.

It is then concentrated by evaporation and the residue is recrystallized several times from methanol.

Yield: 6.8? (38% of theory), melting point 169-17
1°c.

The 2-(2,3-epoxy-propoxy)-carbazole used as starting material is prepared as follows: 2-(2,3-epoxy-propoxy)-carbazole in a mixture of 60.2 rul of 1n-carrying soda solution and 501 rLl of dimethyl sulfoxide. To the solution of hydroxy-carbazole 107, add epichlorohydrin 451.

After stirring for 3 hours at room temperature, the precipitated reaction product is filtered off with suction, washed with methylene chloride and dried.

Yield: 2-(2.3-epoxy-propoxy)-carbazole 147, melting point 206-207°C.

Example 2 3-(3-Improvylamino-2-hydroxy-propoxy)-carbazole 10 g of 3-(2,3-epoxy-propoxy)-carbazole are dissolved in 80 ml of absolute ethanol.

After adding 60 rul of isopropylamine, heat under reflux for 2 hours.

It is then cooled and the precipitate that has settled out is filtered off.

After recrystallization from acetone/alcohol, melting point 178°C
8.4f of crystals (67% of theory) are obtained.

3-(2,3-epoxy-propoxy)-carbazole used as a starting material was prepared by combining 190 ml of dioxane obtained as follows and 98 ml of In-caustic soda solution.
3-hydroxy-carbazole 1 in a mixture consisting of
The solution of 6.3f is stirred at 40-45° C. for 2 hours after addition of 66 ml of epichlorohydrin.

The reaction mixture is then diluted with water and shaken out with methylene chloride.

The methylene chloride phase is washed with water, dried over sodium sulphate and concentrated by evaporation.

16.8P of 3-(2.3-epoxy-propoxy)-carbazole is obtained.

Example 3 4-(3-improvylamino-2-hydroxy-propoxy)-carbasole hydrochloride 4-(2,3-epoxy-
Add isopropylamine 307711 to a solution of Rubazole 357 (propoquine) and heat under reflux for 3 hours.

After the reaction is completed, it is evaporated to dryness. The residue is taken up in methylene chloride and chromatographed on an aluminum oxide column (basic aluminum oxide 3001, active stage ①; developer methylene chloride).

The fractions are concentrated by evaporation, the residue is dissolved in methanol and acidified with 2N ethereal hydrochloric acid.

The precipitate is filtered off and recrystallized from methanol. Yield: 3
．． 1f (62% of theory).

Melting point 234-235°C.

The preparation of the 4-(2,3-epoxy-propoxy)-rubazole required as starting material is carried out analogously to the preparation of 3-hydroxycarbazole in Example 8.

Example 4 N-(3-(carbazolyl-4-oxy)-2-hydroxy-propyl-α-amino-isobutyric acid-methyl ester 4-(2,3-epoxy-propoxy)-carbazole 147 and methyl α-aminoisobutyrate The mixture consisting of ester 71 is heated to 120° C. for 3 hours.

After cooling, it is extracted with acetate, diluted twice with ligroin and filtered with suction.

The filtrate is concentrated by evaporation and the residue is dissolved in ether.

The hydrochloride salt is precipitated by adding ethereal hydrochloric acid.

”Yield: 11S' (52% of theory).

Example 5 6.87 N-(3-(carbazolyl-4-oxy)-2-hydroxy-propyl-α-amino-isobutyric acid 4-(2,3-epoxy-propoxy)-carbazole in 500 ml of methanol) - Heating under reflux for 50 hours with 3.21? of the sodium salt of amino-isobutyric acid.

It is then concentrated by evaporation, the residue is taken up in 500 ml of water and the aqueous solution is seeded with acetic acid.

Acidify and treat with activated carbon.

It is then concentrated by evaporation to 150 ml, during which the compound crystallizes out.

Yield: 5.4 SF (59% of theory).

The hindlimb compound recrystallized from water melts at 252°C.

Example 6 4-(3-tert-butylamino-2-hydroxy-propoxy)-carbazole 1M salt A liquid solution of 8.3 ml of 4-(2,3-epoxy-propoxy)-carbazole in 100 ml of absolute alcohol Add 50 ml of butylamine and heat under reflux for 6 hours.

After the reaction is completed, the residue is evaporated and concentrated using isopropanol 100.
ml and 300 ml of ether,
The solution is acidified with an ethereal solution of oxalic acid.

The precipitate is filtered off and recrystallized from methanol.

Crystal 8.85P with melting point 240-241℃ (theoretical amount and 4
2%) is obtained.

Example 7 A solution of 8.27 g of 1-(2,3-epoxy-propoxy)-carbazole in 100 ml of l-(3-isopropylamino-2-hydroxy-propoxy)-carbazole hydrochloride (anhydrous alcoholic) and heated under reflux for 2 hours.

After completion of the reaction, the mixture is concentrated by evaporation, the residue is dissolved in inpropatol, and the solution is acidified with ethereal hydrochloric acid.

The precipitate is explanted and recrystallized from methanol/isopropanol.

Crystals with a melting point of 215-216°C 8.6? (75% of the theoretical amount
) is obtained.

The preparation of the 1-(2,3-epoxy-propoxy)-rubazole required as starting material was carried out using the 3-(2-
The procedure is analogous to the preparation of 3-epoxy-propoxy)-carbazole.

Example 8 4'-(3-t-Butylamino-2-hydroxy-propoxy)-carbazole-acetate 4-hydroxy-carbazole 3.66 ? , sodium hydroxide 0.8f, 3-chloro-1-t-butylamino-2-propertool 3.32 and ethanol 100ml
The mixture consisting of is heated under reflux for 10 hours.

It is then evaporated in vacuo. The residue is treated with dilute ammonia and the precipitated residue is taken up in methylene chloride.

The methylene chloride solution is separated from the aqueous phase, dried over sodium sulphate and then evaporated to dryness.

The residue was dissolved in acetic acid ester and the solution was brought to pH 4 with glacial acetic acid.
Set to -.

The resulting crystals are filtered and recrystallized from dioxane.

4.27 of 4-(3-t-butylamino-2-hydroxy-propoxy)-carbazole-acetate having a melting point of 168 DEG-169 DEG C. was thus obtained.

In a similar manner the following were obtained: 1-(3-isopropylamino-2-hydroxy-propoxy)-phenothiazine (melting point 203°C), 2-[2
-Hydroxy-3-(phenothiazinyl-1-oxy-
propylamino]propane-2-carboxylic acid (melting point 22
9-230°C), ■-(3-t-butylamino-2-
Hydroxy-propoxy)-phenothiazine (melting point 11
8-120℃), 2-(3-isopropylamino-2-
Hydroxy-propoxy]-phenothiazine (melting point 13
1-132°C), 3-(3-isopropylamino-2-
hydroxy-proxy)-phenothiazine (melting point 162
~163°C), 4-(3-improvylamino-2-hydroxy-phenothiazine (melting point 234°C), 2-(3
-isopropylamino-2-hydroxy-propoxy)
-carbazole (melting point 169-171°C), 3-(3-
isopropylamino-2-hydroxy-propoxy)-
Carbazole (melting point 178°C), 4-(3-improvylamino-2-hydroxy-propoxy)-carbazole hydrochloride (melting point 234-235°C), N-(3-(carbazolyl-4-oxy)-2-hydroxy -Propyl c-alpha-amino-isobutyric acid-methyl ester, N-C3-
(Carbasolyl-4-oxy)-2-hydroxy-globil]-α-amino-isobutyric acid (melting point 252°C), 1-
(3-isopropylamino-2-hydroxy-propoxy)-carbazole-hydrochloride (melting point 215-216°C)
.

Example 9 A mixture consisting of 57 4-hydroxycarbazole, 5Q evichlorhythrin, and 0.1 rrLl peridine is heated under reflux under nitrogen for 10 hours.

Then, it was concentrated by evaporation and filtered. Remove excess epichlorohydrin.

30 ml of tert-butylamine are added to the residue and the mixture is heated under reflux for 12 hours.

The mixture was evaporated to dryness and the residue was dissolved in 50 ml of acetic ester and acidified with glacial acetic acid to give 4-(3-t-butylamino-2-h).

Droxy-propoxy)-carbazole acetate is obtained.

Yield 7.85' (=76% of theory) Melting point 170-17
1°C Example 10 4-(3-amino-2-hydroxy)-carbazole 3
7. A mixture consisting of 6 g of isopropyl bromide, 21 g of potassium carbonate, 0.57 g of potassium iodide and 50 ml of Impropatool is heated at 70° C. for 12 hours under nitrogen.

Then filter, wash the filter residue with Improper tool,
The filtrate is evaporated to dryness, water is added to the residue and extracted with acetic ester.

The acetate ester phase is dried over 1.1 um sodium sulfate, treated with activated charcoal, concentrated to 50 ml and acidified with glacial acetic acid to give 4-(3-improvylamino-2-hydroxy-propoxy)-carbazole. Acetate is obtained.

Yield: 3.2? (-76% of theory), melting point 147-1
48°C Example 11 4-Hydroxycarbasol 3'f! , 1-chlor-3
-isopropylamino-2-propanol hydrochloride 3'? ,
A mixture of 1.51 sodium hydroxide, 10 ml of water and 50 ml of ethanol is heated under reflux for 5 hours under a nitrogen atmosphere.

The mixture is filtered, water is added and extracted with acetic acid ester.

The acetate phase was dried over sodium sulfate, treated with activated charcoal, concentrated to 50 ml and acidified with glacial acetic acid to yield 4-(3-improvylamino-2-hydroxy-propoxy)-carbazole acetate. It will be done.

Yield: 4.9 g (-i 83% of theoretical amount), melting point 147~
148°C Example 12 4-Hydroxycarbazole 3 in 80ml ethanol
To a solution of 7 and 2,3-epoxy-1-inpropylaminopropane 22 was added a solution of 700 m of sodium hydroxide in 20 ml of water at room temperature and 2
Stir for 0 hours.

After the reaction is complete, the alcohol is evaporated in vacuo, the residue is diluted with water and extracted with acetic acid ester.

The acetate phase is dried over sodium sulfate, treated with activated charcoal and acidified with glacial acetic acid to yield 4-(3-isopropylamino-2-hydroxy-propoquine)-carbazole acetate.

Yield: 4.3? (-73% of theory) Melting point: 147° C. Example 13 Solution of sodium 380 ~ in 100 rnl ethanol 1
3f of K4-hydroxy-carbazole and 4 g of 1-(N-benzyl-N-isopropylamine)-3=chloro-2-propatool were added, and the mixture was refluxed under nitrogen atmosphere for 1 hour.
Heat for 0 hours.

Filter and evaporate to dryness in vacuo.

Add water to the residue and extract with methylene chloride.

The methylene chloride phase is dried, treated with activated carbon and concentrated by evaporation.

The residue was dissolved in 100 ml of ethanol, the solution was acidified with 3 ml of glacial acetic acid and the palladium/charcoal catalyst (10%)
The addition of 12 is followed by hydrogenation at room temperature and atmospheric pressure.

After hydrogen absorption has ended, it is filtered and the filtrate is evaporated and concentrated in vacuo.

The residue is recrystallized from acetic ester. 4-(3-isopropylamino-2-hydroxypropoxy)-carbazole acetate 4.5P (#i, 76% of theory) is obtained.

Melting point 147-148° C. Example 14 To a solution of 380 ~ of sodium in 100 ml of ethanol is added 37 of 4-hydroxy-carbazole and 3.52 of 1-(N-benzyl-N-isopropylamine)-2,3-epoxypropane, The mixture is heated at reflux under nitrogen for 10 hours.

Continue to operate in the same manner as in the previous example.

4-(3-isopropylamino-2-hydroxy-propoxy)-carbazole acetate 4.2S'('-i 70% of theory) is obtained.

Melting point: 147 DEG -148 DEG C. Example 15 4-(3-Amino-2-hydroxy-propoquine)-carbazole is dissolved in 50 ml of acetone and 0.57 ml of platinum oxide is added.

The mixture is shaken at room temperature under an atmosphere of hydrogen for 12 hours.

It is then filtered and the filtrate is evaporated to dryness.

The residue was dissolved in 50 ml of acetic acid ester and the solution was acidified with glacial acetic acid to give 4-(3-improvylamino-2-
Hydroxy-propoxy)-carbazole acetate is obtained.

Yield: 3.79 (-87% of theory) Melting point: 147-1
48 DEG C. Example 16 A mixture of 2.31 4-(2-hydroxy-3-amino-propoxy)-carbazole, 2.61 sodium acetate, 8 ml of glacial acetic acid, 10 rnl of acetone and 1 of 25 rnl of water is cooled to Q'C.

To this was added a small amount of IJium 47 under stirring for 30 minutes.

After further stirring for 30 minutes while cooling, add 100 ml of 2N caustic soda.
Add rIll and extract with methylene chloride.

The methylene chloride phase is washed with water, dried over sodium sulfate and concentrated to 50 ml.

4-(3-Improvylamino-2-hydroxy-propoquine)-carbazole with melting point 134°C on cooling 2.2
P (''=82% of the theoretical amount of i) is obtained.

Claims (1)

[Claims] 1. 3-ring diphynylamine derivatives of general formula I: [wherein R1 represents a straight-chain or branched alkyl group optionally substituted with a carboxyl group or an alkoxycarbonyl group] and their In producing a pharmaceutically acceptable salt, a compound of the general formula: is converted into a compound of the general formula ■: Z Rs (ul [wherein one of the groups Y and Z is an amine 7 group and the other is The chemical group R2 represents a hydrogen atom, and its unveiling Y and R2 may together represent a single bond. General formula I
A method for producing a 3-ring diphenylamine, which comprises converting a compound into a pharmaceutically acceptable salt thereof. 2 3-ring diphynylamine derivatives of general formula I: [wherein R1 represents a straight-chain or branched alkyl group optionally substituted with a carboxyl group or an alkoxycarbonyl group] and pharmaceutically acceptable thereof In producing the salt, a compound of the general formula (1) is converted into a compound of the general formula (2) by a method known per se:
R2 represents a hydrogen atom, its unveiling Y and R3 may together represent a single bond, + R3 represents hydrogen], and then the group R1 is introduced later by alkylation, A method for producing a 3-ring diphenylamine, which comprises optionally converting the compound of the general formula (1) thus obtained into a pharmaceutically acceptable salt thereof. 3 General formula I: [In the formula, R1 represents a linear or branched alkyl group optionally substituted with a carboxyl group or an alkoxycarbonyl group] and pharmaceutically acceptable thereof. In order to produce the salt, a 3-ring diphynyl derivative of the formula V: [wherein Y represents an amine group or a reactive group and R2 represents a hydrogen atom] is prepared by a method known per se. Alternatively, the groups Y and R2 may be taken together to represent a single bond.
A method for producing a 3-ring diphynylamine derivative, which comprises converting the compound of I) into a pharmaceutically acceptable salt thereof. 4 3-ring diphynylamine derivatives of general formula I: [wherein R0 represents a linear or branched alkyl group optionally substituted with a carboxyl group or an alkoxycarbonyl group] and pharmaceutically acceptable thereof. In order to produce a diphenyl salt, a 3-ring diphynyl derivative of the formula (1) is prepared by a method known per se. or the groups Y and R2 may together represent a single bond and R3 represents a hydrogen atom], after which the group R1 is subsequently introduced by alkylation, optionally the general A method for producing a 3-ring diphynylamine derivative, which comprises converting a compound of formula (I) into a pharmaceutically acceptable salt thereof.